The differential diagnosis is large and encompasses progressive, unilateral, neurologic disorders due to inflammatory or infectious processes, developmental, metabolic or degenerative diseases, and neoplastic, paraneoplastic, vascular, or even toxic neuropathogeneses (4). It includes focal cortical dysplasia and tuberous sclerosis, mitochondrial encephalopathy, such as mitochondrial encephalopathy with lactic acidosis and stroke-like episodes, brain tumors, focal unihemispheric cerebral vasculitis, degenerative cortical gray matter diseases, and some forms of meningoencephalitis or disseminated encephalomyelitis. Although several diagnostic criteria have been proposed, especially for an early diagnosis of RE, the correct identification of patients with this disease remains a matter of experience, particularly if specific investigative or therapeutic interventions are considered. When a constellation of clinical and laboratory findings highlights the possibility of RE, close follow-up is necessary to assess progression of the disease and eventually confirm its diagnosis.
MEDICAL AND SURGICAL TREATMENTS
The typical evolution of RE is characterized by the development of intractable seizures, progressive neurologic deficits, and intellectual impairment. AEDs quite consistently fail to provide any significant improvement in seizures. This has led clinicians to try a variety of empiric treatments, including antiviral agents and immunomodulatory or immunosuppressive therapies. Surgery, and specifically hemispherectomy, appears to be successful in arresting the disease process. However, the ensuing neurologic deficits due to surgery usually lead to reluctance to carry out this procedure until significant hemiparesis or other functional deficits have already occurred. Apart from the surgical treatment, there is no established treatment for RE. However, with increased experience and knowledge on the pathogenesis of RE, very promising, therapeutic, options are available, and long-term immunotherapies have now a more rational basis for their use and clearer indications (3). These therapies should probably be considered at the early stages of the disease to halt its progression, in cases where surgery is not possible, for instance when important functional brain areas are involved or in severe bilateral or other unusual variants of RE.
Antiepileptic Drug Therapy
Guidelines for AED treatment in RE are difficult to define and have always been empirical. No AED, or any polytherapy regimen, has been proven to be superior (7), and the choice of the ideal AED rests on its clinical efficacy and side effect profile. Because of the nature of this disease, the danger of overtreatment is high. AED pharmacokinetics, toxicity, and interactions may be better determinants of AED selection and combination therapy. EPC is particularly difficult to treat, but AEDs can reduce the frequency and severity of other focal and secondarily generalized seizures. Since the author’s original report on AED efficacy in RE, several new agents have been introduced. Drugs such as topiramate and felbamate that act on excitatory neurotransmitters or those that may affect cortically generated myoclonus, like levetiracetam in EPC, may have a more specific role in treatment. Improved tolerability and better pharmacokinetic profiles and interactions may argue in favor of the newer AEDs.
Antiviral Therapy
Most treatments directed at aborting the progression of the disease were based on the assumption that RE is either an infectious, viral, or an autoimmune disorder. Examples of antiviral treatments are scarce, and only three reports are published: two on the treatment of eight patients with ganciclovir (82), a potent anticytomegalovirus drug, and another on the treatment of a single patient with zidovudine (15). Although some improvement was documented in four of the nine patients, no further reports using antiviral agents in RE have been published; this treatment appeared to be effective only when given early in the course of the disease in three of them raising the possibility that the inaugural insult was maybe indeed viral (82).
Immune Therapy
Evidence implicating humoral and cellular immune responses in the pathophysiology of RE has led to various therapeutic initiatives. A number of case reports and small series suggesting potential therapeutic roles of immune-directed interventions have now been published. These include interferon, steroids, IVIg, plasmapheresis, selective immunoglobulin G immunoadsorption by protein A, and immunosuppression or immunomodulation with drugs such as cyclophosphamide, azathioprine, tacrolimus, rituximab, and even thalidomide. Rarely, such approaches have been associated with sustained cessation of seizure activity and arrest in the progression of the inflammatory process. In the majority of the cases, only transient or partial improvements because of immunomodulator or immunosuppressor use have been noted. Of potential importance is the observation that, to date, the more aggressive immune therapies have been deferred to later stages of the disease, where the burden of the disease is considered to outweigh the toxicity of these interventions. The challenge is to develop safe therapeutic protocols that can be tested in patients soon after the diagnosis and at a time when less damage has occurred and the process may have a better chance to respond to therapy. Eventually, regimens that strike the proper balance between safety and efficacy in typical RE could be applied to the more unusual variants (3).
Interferon-α
Intraventricular interferon-α has been tried in two children (80,81) with the rationale that interferons have both immunomodulating (enhancement of phagocytic activity of macrophages and augmentation of the cytotoxicity of target-specific lymphocytes) and antiviral activity (inhibition of viral replication in virus-infected cells). In both cases, improvement of the epileptic and neurologic syndrome was observed. Interferon β-1b has been used in a case of adult-onset RE, concomitantly or sequentially with steroids and immunosuppressants, and authors reported that treatment reduced seizure frequency, prevented exacerbation of other CNS symptoms, and slowed development of brain hemiatrophy (34).
Steroids
Relatively low- and high-dose steroid regimens were used either alone or in association with other agents such as IVIg. Initial reports were somewhat discouraging (56), but eventually, the use of high-dose intravenous (IV) boluses led to encouraging results. When applied during the first year of the disease, pulse IV steroids were effective in suppressing, at least temporarily, the inflammatory process (13,14,20). The proposed modes of action of steroids include an antiepileptic effect, an improvement of BBB function—and hence reduction of entry into the brain of potentially deleterious toxic or immune mediators—and a direct anti-inflammatory effect. Because of a less favorable response and of the adverse effects of prolonged high-dose steroids, Hart et al. (13) suggested the use of IVIg as initial treatment followed by high-dose steroids, or both, to control seizures and improve the end point of the disease. Granata et al. (25) have proposed a protocol for administration of immunomodulatory treatments in children and adults with RE. Corticosteroids were given alone or in combination with plasmapheresis, IVIg, protein A Ig immunoadsorption, or cyclophosphamide with positive but time-limited clinical responses in 11 of 15 patients. The long-term efficacy of steroids in RE remains unknown, but there are reports supporting steroid use (13,14,25), specifically pulsed steroid courses to stop status epilepticus (13,25). Also, one has to weigh the risks of long-term steroid therapy and maybe more importantly of delaying unduly the most appropriate treatment for this severe condition, which, in the majority of the patients, remains on the long run surgery of the affected hemisphere.
Immunoglobulin
The use of IVIg in RE was first described by Walsh (104) in a 9-year-old child who received repeated infusions of IVIg over a period of several months with initial improvement but later followed by protracted deterioration and cessation of the treatment. Eight subsequent studies reported on the effect of IVIg, alone or in combination with other treatment modalities (13,20,22,23,25). These reports show similar results with initial benefit, but with a much less clear-cut, long-term effect. IVIg is usually much better tolerated than steroids. The basis for a potential therapeutic effect of immunoglobulin in RE is not known but may reflect the functions of natural antibodies in maintaining immune homeostasis in healthy people. Leach et al. (22) showed a delayed but more persistent response in two adults and suggested that IVIg is more effective in adults than in children. They also proposed that IVIg may have a disease-modifying effect. This phenomenon is probably real but, to date, no one has shown that the early use of immune therapy can modify the long-term course of RE. In a recent report (105), guidelines on the use of IVIg for neurologic conditions were presented by a Canadian expert panel. The expert panel stated that in view of the seriousness of potential adverse events and current lack of data surrounding their frequency and in view of the relatively high costs, IVIg should be prescribed only for appropriate clinical indications for which there is a known benefit. They identified five reports of IVIg use for RE and recommended that IVIg may be an option as a short-term, temporary measure for patients with RE.
Plasmapheresis and Selective IgG Immunoadsorption
Plasma exchange is used with the assumption that circulating factors, likely autoantibodies, are pathogenic in at least some patients (20,25,84,87,88). The majority of patients treated with apheresis showed repeated, and at times dramatic, but transient responses. Because of the lack of long-term efficacy, the complications, and the expense, plasmapheresis should probably be used as adjunctive therapy and may be especially useful in patients with acute deterioration, such as status epilepticus.
Immunosuppressive and Immunomodulation Therapy
Immunosuppressants are used in other autoimmune disorders and also in the prevention and treatment of transplant rejection. They act against the activation of T cells, which, in view of the recent findings of cytotoxic T-lymphocyte–mediated damage in RE, may lead to their acquiring a more prominent role in medical treatment.
Few studies reported on the use of cyclophosphamide in no more than half a dozen patients (20,25,87). It was proposed that intermittent cyclophosphamide may well replace steroid therapy because it is associated with less risk of systemic complications. The experience in this small number of patients is suggesting that neither acute nor chronic use of cyclophosphamide produces significant change on seizure frequency or disease progression.
Seven patients with RE were treated with oral tacrolimus (median follow-up, 25.4 months) with superior outcome regarding neurologic function and progression rate of atrophy but no better seizure outcome as compared to 12 untreated RE patients (106). There were no major side effects. A randomized prospective study comparing IVIG and tacrolimus in RE is currently underway (107).
Following demonstration of antibodies directed against brain tissue in RE and the real but modest effects on disease with immunomodulation (steroids, IVIg, apharesis, and immunosuppressants), a pilot study is now also ongoing with rituximab to directly target the B cells thought to be involved in the process (108). Recently, a single case report described a patient with RE that entered a seizure-free period after being treated with IgG immunoadsorption and intravenous rituximab (109). This suggests that rituximab, a monoclonal anti-CD20 that causes depletion of B cells, may also have an effect on T cells.
Thalidomide was used for the first time by Ravenscroft et al. (110) in a 7-year-old male with RE and high level of CSF tumor necrosis factor-α, leading to a dramatic and sustained clinical response. This prompted a second case report of a 13-year-old girl with very refractory RE since age 5 in whom thalidomide was administered because of a life-threatening condition (111). Prior to thalidomide administration, she received sequentially acyclovir, IVIg, IV and oral steroids, a partial left parasagittal frontoparietal resection, plasma exchanges, and cyclophosphamide. After thalidomide was started, she rapidly improved and during the following 3 years received oral thalidomide 300 mg/day (in addition to valproic acid, clonazepam, piracetam) with a significant and sustained reduction in the frequency and intensity of her seizures. She only developed moderate neutropenia attributed to the drug.
Other Nonsurgical or Semi-Invasive Approaches
Repetitive transcranial magnetic stimulation by reducing cortical excitability can suppress at least momentarily seizure activity and hence may be a useful noninvasive palliative tool in some cases; only one case has been reported (112) and clearly further explorations are needed. Two other patients with adolescent and adult-onset RE (both had brain biopsies) received transcranial direct current stimulation at 1- and 2-mA intensity for 60 minutes in four sessions over a period of 2 months. There were no complications. One patient showed a significant reduction in seizure frequency and the other became seizure free (at follow-up evaluations at 6 and 12 months), and both patients showed improvement in cognition and alertness (37). Finally, a single patient, also with an adult-onset RE, experienced a significant and persistent (over 2 years) reduction in seizure frequency (>50%) and improvement of her neurologic and cognitive condition after vagal nerve device implantation and vagal nerve stimulation (36).
Botulinum toxin was marginally used in attempts to control focal seizures or hyperkinetic movements in RE. To date, only two patients were reported with such treatment (113,114). Finally, to our knowledge, no patient with RE showed significant benefit from deep brain stimulation.
Surgery
The only effective surgical procedure seems to be the resection or disconnection of the affected hemisphere (63,115,116). Alternative procedures such as partial corticectomies, subpial transection, and callosal section have limited results and did not render patients seizure free (117–120). Kossoff et al. (116) demonstrated the benefits of hemispherectomy in children with RE. They showed that 91% of 46 children (mean age at surgery, 9.2 years) with severe RE who underwent hemispherectomy (in the majority hemidecortication) between 1975 and 2002 became seizure free (65%) or had nondisabling seizures (26%) that often did not require medications. Patients were walking independently, and all were talking at the time of their most recent follow-up, with relatively minor or moderate residual speech problems. Twenty-one patients had left-sided pathology (presumably involving the dominant hemisphere in most) with a mean age at surgery of 8.8 years.
Hemispherectomy, hemidecortication, functional hemispherectomy, or hemispherotomy have proven efficacy for control of seizures in patients with RE (3,25,63,115,116,121–126). The decision on how early in the course of the disease surgery should be undertaken depends on the certainty of the diagnosis, the severity and frequency of the seizures, and the impact on the psychosocial development of the patient. The natural evolution of the disease and the severity of the epilepsy often justify early intervention, even prior to maximal neurologic deficit. Finally, involvement of the dominant hemisphere by the disease process provides important observations on brain plasticity, especially on the shift of language (4,122,127). Recent reports looking at language outcomes after long-term RE, serial Amobarbital tests, functional MRI studies, and hemispherectomy illustrate the great plasticity of the child’s brain and the ability of the nondominant hemisphere to take over some language function even at a relatively late age. The decision about such a radical procedure requires considerable time and thought, and the psychological preparation of the patients and their families is essential (3,63,128,129).
CONCLUSION AND FUTURE PERSPECTIVES
Rasmussen’s encephalitis, although a rare disorder, is now much better delineated and understood by the wider clinical and scientific community. However, recognition of the disease in a naive patient to make an early diagnosis continues to be a challenge. Although confirmation of the clinical diagnosis of RE rests on pathologic findings, in vivo combinations of diagnostic approaches such as clinical course, scalp EEG findings, and high-resolution MRI suggest the diagnosis with a high degree of accuracy. The syndrome, however, appears more clinically heterogeneous than initially thought; localized, protracted, or slowly progressive forms of the disease have now been described suggesting that distinct pathophysiologic mechanisms may be at play. Evidence implicating immune responses in the pathophysiology of RE has accumulated involving both B- and T-cell–mediated processes, but the mechanisms by which the immune system is activated remain to be elucidated. The identification of autoantigens provides evidence that RE can be associated with an immune attack on synaptic antigens and impaired synaptic function leading to seizures and cell death. In addition, T-cell–mediated cytotoxicity may lead to neuronal damage and apoptotic death. Identification of the initiating event (possibly the antigen that triggered the autoimmune response) and of the sequence of immune responses occurring in the course of the disease will hopefully allow timely and specific short- or long-term immunotherapy. Patients with RE, however, usually present with rapid progression, and questions on the type and timing of surgical intervention are still being raised. Most patients will fare better with earlier surgery, and only hemispherectomy techniques can provide definitive and satisfactory results with good seizure, cognitive, and psychosocial outcome.
ACKNOWLEDGMENT
I thank Drs. Frederick Andermann and Amit Bar-Or for thoughtful comments.
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